Arginine vasopressin (AVP) is a neurohypophyseal neuropeptide produced in the hypothalamus, and is involved in many biological processes in the circulatory system, the peripheral nervous system (PNS), and the central nervous system (CNS). In particular, AVP acts as a neurotransmitter in the brain. Several pharmacologically significant vasopressin receptor subtypes, including vasopressin V1a, V1b, and V2, have been identified. Such vasopressin receptors are involved in several psychiatric, psychological, and behavioral disease states including depression, anxiety, affective disorders, and stress, as well as non-opioid mediation of tolerance for pain. Vasopressin receptors are also involved in a number of metabolic processes including water metabolism homeostasis, renal function, mediation of cardiovascular function, and regulation of temperature in mammals.
Structural modification of vasopressin has provided a number of vasopressin agonists (see, Sawyer, Pharmacol. Reviews, 13:255 (1961)). In addition, several potent and selective vasopressin peptide antagonists have been disclosed (see, Lazslo et al., Pharmacological Reviews, 43:73-108 (1991); Mah and Hofbauer, Drugs of the Future, 12:1055-1070 (1987); Manning and Sawyer, Trends in Neuroscience, 7:8-9 (1984)). Further, novel structural classes of non-peptidyl vasopressin antagonists have been disclosed (see, Yamamura et al., Science, 275:572-574 (1991); Serradiel-Le Gal et al., Journal of Clinical Investigation, 92:224-231 (1993); Serradiel-Le Gal et al., Biochemical Pharmacology, 47(4):633-641 (1994)). Finally, the general structural class of substituted 2-(azetidin-2-on-1-yl)acetic acid esters and amides are known as synthetic intermediates for the preparation of β-lactam antibiotics (see, U.S. Pat. No. 4,751,299).